Arylsulfonyl derivatives of bicyclic guanidines



United ARYLSULFONYL DERIVATIVES F BICYCLIC GUANIDINES Arthur Ferguson McKay, Pointe Claire, Quebec, and Maria-Elisabeth Kreling, Montreal, Quebec, Canada, assignors to Monsanto Canada Limited, Ville LaSalle, Quebec, Canada No Drawing. Application October 28, 1957 Serial No. 692,576

Claims priority, application Great Britain April 29, 1957 4 Claims. (Cl. 260-2399) stirred aqueous solution of the bicychc amine is added an excess (suitably up to about two equivalents), of the appropriate arylsulfonyl chloride and ether. mixture there is then added slowly a solution of aqueous alkali, in an amount not less than that equivalent The above reactions are carried on substantially at, or slightly above, room temperature, but preferably not in excess of about 35-40 C;

While the above describes a preferred practice for carrying out our invention, it is to be understood that the invention is not limited thereto. For "example, anhydrous pyridine may be used both as reaction solvent and HCl acceptor, and temperatures substantially'ab'ove C. recovering the reaction product by dilution of the mixture with water. The reaction may also be carried out using aqueous acetone as the solvent.

rates Patent D Of the compounds contemplated in this invention, the

l-p-toluenesulfonyl, l-p-amiriobenzenesulfonyl and 1-p-' acetylaminobenzenesulfonyl derivatives have been demonstrated to possess excellent bacteriostatic properties. For example," the sulphonamides of' the invention are effective bacteriostats against the following organisms: Staph. pyogenes (R), Sarcina lutea, Strept. faecalis, Aero. izi'o-f S. pullorum, Ps. aeruginosa ln genes, E. coli #198, mirabilz's, Pr. vulgaris, Slap/2. pyogenes (S). H The compounds of the invention may be prepared -for use as bacteriostatic agents.- They may be with an active or mert complementary. material or carrier. The caror substances, or both inert and active substances.

The l-p-aminobenzenesulfonyl compounds are readily prepared from the corresponding acetyl derivatives. For example, an aqueous alcoholic solution of the acetyl comhydro-l-imidaz (1,2a) imidazole scope.

EXAMPLE I J-p-t0luenesulf0nyl-2,3,5,6-tetrahydr0-1-imidaz (1,2-a)

x imidazole p-Toluenesulfonyl chloride (M. P. 66- 69 C.; 1.9 parts) and ether (12 parts by volume) were added to this solution. To this stirred mixture was added the calculated amount of 3.75 N aqueous sodium hydroxide solution (2.6 parts by volume) over a period of 40 minutes. The stirring was continued for a further fifteen minutes after which the precipitate was removed by filtration and dried, yield 1.3 parts (99%).

The melting point of the crude product was raised from 180-183 C. to 182-184 C. by crystallizing from boiling ethyl acetate containing a little methanol. Analytical results obtained were as listed in the Table I.

EXAMPLE II I -p-acetylaminobenzenesulf0nyl-2,3,5,6-tetrahydro-1 imidaz (1,2a) imidazole (n=m=2, Ar: acetylaminophenyl) This compound (M. P. 236-245 C.) was prepared in 94.5% yield by the reaction of p-acetylaminobenzenesulfonyl chloride (M. P. C.) with 2,3,5,6-tetra-' the conditions'described in Example I. A sample of the crude product melted at 270-2715 C. after it was crystallized three times from' nitromethane. units obtained are listed in the Table I.

EXAMPLE III] 1 -p-t0 luenesulf0nyl-A J1exahydrO-I,4,8-pyrimidazole (n=3, m=2, Ar=p-tolyl) To a stirred solution of A -hexahydro-1,4,8-pyrimidazole (5.0 parts) and p-toluenesulfonyl chloride (7.60

droxide solution).

, After the dropwise addition of the sodium hydroxide I solution, which required twenty minutes, the reaction mixture was stirred for an additional forty minutes at room temperature. yield 11.06 parts (99.5%). This product was purified by crystalli'zing from The product was recovered by filtration,

ethyl acetate. Melting point and .analytical data obtained are listed in the Table I.

EXAMPLE IV I-1? tictylaminobenzenesuljonyl-A -hexaydr0-1,-'l,8- pyrimidazole (n=3, m=2, Ar=p-acetylaminophenyl) This compound was prepared by the method described in the'above examples. Results obtained are listed in the Table (16.67 parts) under Analytical 3 EXAMPLE v 1-p-t0luenesulfonyl-A -1,4,9-triazabicycl (5.3.0.) decene (n=4, m= 2, Ar=p-.tolyl) This compound was prepared by the method described in Example III, above. Results obtained are listed 'in Table I- EXAMPLE v1 1 1 -p-acetylaminobenzenesulfonyl-A -1,4,9-triazabicycl0 (5.3.0) decene (r1=4, m=2, Ar=p-acetylaminophenyl) This compound was prepared by the method described in Example III, above. Results obtained are listed in Table I.

EXAMPLE VII 1 -p-nitrobenzenesulfonyl-23,5,6atetmhydroe1-imidaz (1 ,Z-a) imidazole (n and m=2, Ar=p-nitrophenyl-) This compound was prepared by the procedure outlined in Example III, above. Results obtained are listed in Table I.

EXAMPLE VIII 1-p-amin0benzenesulfonyl-Z,3,5,6-tetrahydr0-1-imidaz (1,2-11) imidazole (n and "1:2, Ar=p-aminophenyl-) A mixture of 1-(p-acetylaminobenzenesulfonyl)-2,3,5,6- tetrahydro-1-imidaz (1,2-a) imidazole (9 parts), ethanol (200 parts) and 5 N sodium hydroxide solution parts) was heated under reflux. After five minutes a homogeneous solution was obtained and the refluxing was continued for a further ten minutes. The solution on cooling and diluting with water deposited crystals, yield 6.7 parts by weight (85.8%). The crude product, which melted at 181-184 C., was purified by crystallization from acetone-hexane (4:1) solvent. The properties of this compound are given in Table I.

EXAMPLE IX 1-p-aminobenzenesulfonyl-A -l ,4,9-triazabicyclo (5.3.0) decene (11:2, m=4, Ar=p-aminophenyl-) This compound was prepared from l-p-acetylaminobenzenesulfonyl-M-l,4,9-triazabicyclo (5.3.0.) deoene by the procedure'described in Example VIII, above. The product was crystallized from acetone-hexane (2:1) solvent. Results obtained are listed in Table I.

TABLE I.ARYLSULFONYL DERIVATIVES OF THE BICYOLIO GUANIDINES Yield,

Compound Percent M. P. 0.)

Formula C H N S Found Calcd.

Found Calcd. Found Calcd. Found Calcd.

1 p Toluenesulfonyl 2,3,5,6 tetrai hydro-l-lmidaz (1,2-a) imidazole- 1 p-Acet-ylamtnobenzenesultonyl-Z,

3,5,6-tetrahydro-1-tmtdaz (1,2-a) imidazole 94. 5 270-271. 5 1 p Toluenesul ionyl-M-hexahydrol Ci2H15Ns02S 54. 31 54. 36 5. 70

C13H16N403S 50. 61 50. 66 5. 20 CnHnNaOzS 55. 89 50. 22 0. 13 OllHlBNQOiS 52. 15 52. 30 5. 63 5. 71 17. 39 17. 69 9. 94 9. 95 CitHisNaOzB 57. 31 57. 12 6. 53 6. 67 1'1. 32 14. 51 10. 9 3 11. 16 I Ct6H20N403S 53.55 53. 33 5. 99 5. 13 15. 66 16. 52 9. 5'1 9. 43

CuHnNtCuS 44.58 44.72 4.08 4.10 18.91 19.36 10.82 10. 74 GuHuNtOaS 49.60 49.23 5.30 5.30 21.04 21.09 12.04 12.05

TABLE II.-EVALUATION OF SULFONAMIDES AS BACTEBIGSTATS Test Organisms Pr. vulaaris Staph. pyogmea (S) II III MgJml. Mgjml.

I 1 Mg./m1.

1 l-p-acetylarnlnobenzenesulfonyl-A-1,4,9-trlazabieyclo (5.3.0) deeene.

IL l-p-tol III. l-p-tol uenesulfonyl-M-l 4,9rtriazabicyel0 (5.3.0) decene. uenesulfonyl-A -hexahydro-l,4,8-pyrim1dazole.

IV. l-p-acetylammobenzenesulfonyl-A -liexshydro-l,4,8-pyrtmldazole. V. l-p-acetylamtnobenzenesuifonymfi,5,6-tetrahydro-1-1m1daz (1 2-11) ingtldazole. V-I. l-p-amtnobenzenesulionyl-zlt,5,6-tetrahydro-1-xmldaz (1,2-a) nntdazol stated.

e. This table shows minimum concentrations efleettve to prevent growth of the organisms 5 We claim: I. A sulfonyl derivative of bicyciic guanidine corresponding to the general formula 2 to 3 and R is a radical selected from the group con- 10 sisting of para-nitro phenyl, para-amino phenyl, paraacetylamino phenyl and para-methyl phenyl.

References Cited in the file of this patent UNITED STATES PATENTS 2,229,784 Winnek Jan. 28, 1941 

1. A SULFONYL DERIVATIVE OF BICYCLIC GUANIDINE CORRESPONDING TO THE GENERAL FORMULA 